Removal of water from p-acetylsulfanilylchloride with ketones



May 23, 1950 H. H. RICHMOND 2,503,930

REMOVAL OF WATER FROM PACETYLSULFANILYLCHLORIDE WITH KETONES OriginalFiled April 8, 1948 2 Sheets-Sheet 1 MPM/ Vf cnaf 4. J. a. www/W4@ Maf@mW/fr 0f Wwf/e ATTORNEY May 23, 1950 H. H. RICHMoND 2,508,930.

REMOVAL OF' WTER FROM PACETYLSULFANILYLCHLORIDE WITH KETONES l OriginalFiled April 8, 1948 2 Sheets-Sheet 2 fecal/ered e one f INVENToR.

Patented May 23, 1950 REMOVAL OF WATER FROM DACETYLSULF` ANILYLCHLORIDEWITH KETONES Henry H. Richmond, Pittsburgh, Pa., to United States RubberCompany, New York, N. Y., a corporation of New Jersey Originalapplication April 8, 1948, Serial No. 19,703. Dividedand thisapplication April 2,3, 1949, Serial No. 89,218. In Canada April 6, 19489 Claims. (Cln. 26o- 543) invention relates to novel improvementsL inthe manufacture of sulfaguanidine, particularly in that process for themanufacture of sulfaguanidine wherein p-acetylsulfanilylchloride iscondensed with quanidine with subsequent removal of the acetyl group.

VSulfaguanidine has heretofore generally been made by the condensationof guanidine with pacetylsulfanilychloride using an aqueous solution ofalkali metal hydroxide. generally sodium vhydroxide, and awater-miscible organic liquid,

such as acetone or isopropyl alcohol. The pacetylsulfanilylguanidineformed by this reaction is then hydrolyzed, by heating with aqueoushydrochloric acid or with aqueous alkali metal hydroxide whereuponsulfanilylguanidine is recovered from the reaction mixture in anysuitable Way.

I have found that when the procedure outlined in the preceding paragraphis folloWed-the'yield of4 p-acetylsulfanilylguanidine formed -by thecondensation of quanidine and p-acetylsulfanilylchloride is in theneighborhood of 'I0 percent. I have found that the principal reason forthis low yield is the formation of considerablebis-(acetylsulfanilyl)-guanidine as by.'pro.duct. Formation of thisby-product can be avoidedi only to a small extent by limiting thequantity of pacetylsulfanilylchloride used.

The principal object of .the present invention is to provide a method ofmaking pfacetylsulfanilylguanldine which avoids the disadvantageous lowyield of prior art practice. Another object is to provide an improvedmethod of making sulfaguanidine. Another object is to provide a noveland advantageous method of separating p-acetylsulfanilylchloride rfromwater.

Many other objects and advantages of the presfacture ofacetylsulfanilylguanidine and of sulfaguanidine in accordance with myinvention.

I have now found unexpectedly that if a ketone having the generalformula OHs-(UJ-R where R is a C2 to C4 alkyl or alkenyl group is usedin conjunction with concentrated aqueous alkali metal hydroxidesolution, as the reaction medium, the condensation of guanidine withp-acetylsulfanilylchloride to form p-acetylsulfanilylguanidine inincreased yield, often as high as approximately 90 percent based on theguanidine, can be readily effected. The increase in yield as a result ofthe use of such ketones in conjunction with concentrated aqueousalkaliin Aaccordance with my invention appears to be attributable to thefact that very little by-product bis-(acetylsulfanilyl) guanidine isformed. This is a novel and unexpected result for which it is difficultto propose any specic reason. Other organic liquids which were triedsuch as ethylene Ydichloride or toluene were found to be whollyunsatisfactory since no sulfonamide was formed,

the product formed when these other solvents were used beingguanidiniumacetylsulfanilate. When acetone is used, an objectionable amountv of thebis-(acetylsulfanily1) -guanidine is formed.

The ketones used in accordance with the present invention are normallyliquid ketones, i. e.I are liquid at ordinary temperatures such astemperatures of from 10 to 30 C. used in carrying out the condensationstep of my invention, and

boil below 60 C. at 20 mm. pressure so that they can be removed readilyby fractional distillation of the reaction mixture as shown below. Thethree most highly preferred ketones for use in my invention are methylethyl ketone, methyl isobutyl ketone and mesityl oxide. The ketones usedin practicing my invention are characterized'by `being relativelyimmiscible with water and by being immiscible with the aqueous alkalimetal hydroxide solution used in the process. I prefer to employ thoseketones answering to the above description which are unsubstituted, i.e., which are free from substitution with other groups. The ketones usedin practicing my invention are inert with respect to the other materialspresent `in the reaction mixture.

The following dialkyl ketones are useable in the practice of myinvention: Methyl ethyl ketone,

methyl n-propyl ketone, methyl isopropyl ketone, methyl n-butyl ketone,methyl isobutyl ketone, methylsec-butyl ketone and methyl tert-butylketone. The following ketones exemplify those wherein R in the formula v0 OHa-g-R is a1keny1; mesityl oxide (methyl isobunm ketone), methylvinyl ketone, methyl allyl ketone and methyl crotyl ketone. R in theformula may be any Ca to C4 alkyl or alkenyl group.

in marked contrast to the prior art manufacture of sulfanilylguanidinesince when acetone'is employed it is necessary to limitthe amount ofacetylsulfanilylchloride used in order '.to mavoid formation of theby-product ;zbis,-iacety1sul fanilyl) -guanidine as much as possible.

The amount of the selected ketone'usedin practicing my invention mayvary widely. I genierally -use such Lrelative proportions of "ketoneandaqueous yalkalithatathellietone phase of; the KAreaction mixture isVlarger than the aqueous I prefer f to employ the -ketone in van 'amountsuch that the volume ratio of theketone `phase `tothe aqueousphaseranges from 2:1 to 411. Because of the-immiscibility ofthe aqueousconcentrated -alkalisolution andthe ketone in one another, use oftheketone:-and of the aqueous -alkali Vmetal hydroxide solution in therelativejproportions just mentioned produces a reaction vmixture whereinketone 'phase `and the aqueous phase are present insubstantially'corresponding relative proportions.

The concentration of theraqueousalkali-used in practicingmyinventionshould be-high, i.v e., at least 20 percent' kby'weightlrangingftherefrom upwardly to 30 percentbysweight. Use of'this highconcentration of alkalimetal hydroxide'depresses the ionization of theguanidine. -If-the-f40 guanidine is permittedl to ionize in 4diluteaqueous alkali to formguanidinium ion,v then lthe lreaction product isguanidiniumfaoetylsulfanilate. While Y any alkali metal hydroxide maybeemployed in lpracticing my invention, I usually employ sodium A4,5 A

hydroxide.

'As is well-known, 'the acylrgroup'on the sulfaniliylchloride condensedwiththeguanidine is usually acetyl although it maybe any other Vlower*fatty acid group having-notmore than four-'car- 5o bon atoms or mayeven-be benzoyl.

Any suitableL form of `guaiiidine vmayL be employed in practicing myinvention. I almost'in- 'variably use guanidinein the form` of-a'suitable guanidine salt, such as guanidinefnitrate. Hselection of asuitable form of the -guanidine does not per se constitute any part ofthe present in- 'ventioni In carrying out the `condensationl of theacetylsulfanilylchloride with the guanidine, I usually employ aconsiderable molarexcess of alkali metal hydroxide over the guanidine,the molar ratio of alkali metal hydroxide to Lguanidine generally beingvfrom`2zl to 4:1.

I generally carry outthecondensation byforming in any suitable Way amixture of the guanidine .85

salt, the aqueous sodiumhydroxide solution and a part or all of theselected` ketone, andadding with agitation and maintenance of thetemperature at between and 30D C the p-acetylsulfanilylchloride over a`siisbtantial period. The im acetylsulfanilylchloride may be in anysuitable form. Usually it is added gradually either `as adrypowder or asasolution ina portion of 'the ketone sufficient to dissolve the same.

The -f'55 the reaction .mixture stirredduring ano. roften V .follow-mg.Y addition of y.therwaten .over a periodroftime wnicnmayrange largeketone phase, the agitation is not always entirely satisfactory sincethe acetylsulfanilylguanidine which precipitates during the reactionoften tends to cling to the sides of the vessel occludingzunreactedguanidineand.acidlchloride I have' found, howeverfthatthisf'difculty maybe avoided by the slow addition of a limited A,amount of water after theacid chloride has been -added and allowed toreact with stirring, theaddition of .such additional water being commenced after a suitableperiod of time has elapsed following completion'of the addition of theacid chloride; -by proceeding in this manner theprecipitated^`materia1"which clings to the sides of the vessel isfremoved. Only suicient additional `water;shouldibe :added in thismanner 'to eifect tliisfresultand the addition of the water shouldbemadeslowly with stirring to obtain the maximuni benefit of the wateradded. Preferably addition of this water is not commenced untilvatlleast20i:ninutes have elapsed'foliowing completion vof additionkof'a'cid chloride to the reactionmixture. Theadditional Water-may be.added gradually Vinany desired manner, Y,either continuously orportionwiseLportionwise;addition generally being morek convenient Amabatchtype ofoperation. The amount of water added in y.this -manner may.vary widely but preferably rangesli'romlu percentlto :suupercent byvolume based on the volume of thelketonepresent in `The reaction mixtureis from-SU-minutesto V:shoui's .ai'ter initiation of Theacetylsulfaguanidine i. appears as .a Iprecipitate in the resultingreaction mixture andmay be recovered therefrom .in any -suitabie manner.

At the 4present y time the standard method used for the manufacture.of-,suiI-aguaniuine involves the :isolation v of the Yintermediateacetyisuifalguanidine iiorined by the .condensation of guanidine `andacetylsuifanilyichloride. Unfortunately the acetylsuiianiiylguanidineintermediate is formed insa stateiof very iinesubdivisionso 4thatseparation in conventional manner :from the ymothenliquoryas by`filtration is =very slow and diicult.

l Hovveverr' Iihaveifound :a `method wherebyv the diiiioulty ofseparation'offtheinterinediate acetylsulfaguanidine .is A- circumvented.I :have '.found that there vis no needfto isolatei this intermediatebutzthat the reaction .mixture may be ,treated `to removethe `ketoneand'thence carried .through `the hydrolysis stage in which the-acetylgroup is nremoved by hydrolysis Lto `vgive 4the desired productsuliaguanidine. In this fway the considerable labor and equipment whichwould-be required to effect the filtration of the -acetylsulfaguanidineare obviated. My method also obviates the necessity 4'for the-storagevlof l-the intermediate and its reloading into a reaction-'vesselwhereinthe hydrolysis'is 'to becarried out. I have found a 'methodv'ofvconducting the lhydrolysis in the same reactionvessel as that'whereinthe condensation of the `acid chloride with the guanidinewas effected.

Avoidance of the necessity-of isolating the acetylsulfaguanidine by mymethod has a number of other advantages. I have found that the ketonesemployed may be recovered from the reaction mixture 'to Van extent ofmore vthan 90 fpercent by Vsimply @applying VKa '.lpartial vacuumHowever, with the small aqueous phase and the @15 tothe lreactionivesselyaf-ter the condensationzof g'uanidine andacetylsulfanilylchloride and distilling oi the ketone with stirring andheating of the reaction mixture to a temperature below 60 C. andpreferably from 40 to 50 C. The vacuum is so adjusted that the reactionmixture has the foregoing temperature and that the ketone distillsfreely. The presence of Water in the mixture undergoing distillationappears to expedite removal of the ketones therefrom, since the ketonesform azeotropes with water, which azeotropes boil considerably below theketones. By proceeding in the foregoing manner, the ketone which forms aconsiderable part of the raw material cost of the process can be readilyrecovered forlre-use and in this Way costs can be greatly reduced.Furthermore, if it were attempted to rst lter off theacetylsulfaguanidine, the recovery of ketone would be renderedconsiderably more difficult since the motheriliquor would be dilutedwith wash water and much larger volumes would require distillation.Additional equipment would be required in such case for the storage andthe distillation and the recovery of the ketone would not be as greatbecause of the additional handling and the decrease in the efficiency ofrecovery attributable to the increased volume as a result of thedilution. Another advantage of proceeding in the foregoing manner andusing the reaction mixture containing the acetylsulfaguanidine directlyfor the hydrolysis is that there is a saving of sodium hydroxide sincethe excess of sodium hydroxide which was used in the condensation ofguanidine and acetylsulfanilylchloride is made use of in the hydrolysis.In a two-step process, this sodium hydroxide would be lost in the motherliquors. Another advantage is that there is no heat loss after therecovery of the ketone since the warm reaction mixture can be useddirectly for the hydrolysis, whereas ifi the acetylsulfaguanidine isfiltered off and the solvent is recovered from the mother liquors, theheat inthe mother liquors is lost. Another advantage is the considerablesaving in time for each batch of sulfaguanidine because of theelimination of several operations; this increases considerably theproductivity of the plant.

Following distillation of the ketone, the hydrolysis of theacetylsulfaguanidine is carried out, preferably by adding additionalwater and -so dium hydroxide and heating with agitation at 60 to 80 C.for from 1 to 3 hours.

The relative amounts of sodium hydroxide and Water present in themixture undergoing hydrolysis are not especially critical. The amountsof water and of sodium hydroxide added to the reaction mixture at thispoint preparatory to effecting the hydrolysis may conveniently be suchthat there is present in the hydrolysis mixture a'total of 2.5 to 7.0moles free NaOH and a total of from 1000 to 2000 cc. of water per moleof acetylsulfanilylguanidine. The excess of sodium hydroxide remainingafter the condensation of guanidine and acetylsulfanilylchloride canreadily be calculated since each mole of the latter uses up one mole ofsodium hydroxide and each mole of guanidine nitrate uses up one mole ofsodium hydroxide. With the lower quanity of alkali the reaction time forthe hydrolysis should be increased in order to carry the hydrolysis tocompletion. The concentration of thel alkali solution present in thehydrolysis mixture may vary from to 20% sodium hydroxide. The quantityof water present should be such to. insure good stirring which mayrequire a weight ratio of solution of sodium hydroxide to acetylsul-Following the hydrolysis step, the precipitated sulfaguanidine productis recovered from the resulting reaction mixture in any suitable manner,usually by cooling to room temperature and filtering. I find itdesirable to filter off the sulfaguanidine shortly after cooling to roomtemperature since in some cases a by-product precipitates upon prolongedstanding of the hydrolyzed mixture. The sulfaguanidine preparedaccording to my invention is satisfactory in its crude state to beemployed as a raw material for the manufacture of other sulfa drugs,i.e., sulfamerazine, sulfamethazine and sulfadiazine. If a U. S. P.grade is desired, the crude product can be readily purified bycrystallization from water or other solvents in a known manner.

As disclosed above, the condensation of guanidine andacetylsulfanilylchloride takes place best in concentrated sodiumhydroxide. Acetylsulfanilylchloride is usually made by the treatment ofacetanilide with chlorosulfonic acid and subsequent drowning in iceWater. The precipitated acetylsulfanilylchloride is then separated andwashed. This crude acetylsulfanilylchloride contains a large quantity ofmoisture and has a pasty consistency; the moisture content may be ashigh as 75%. Because of this the use of this very wet material maydilute the aqueous solution of guanidine and sodium hydroxide to such anextent as to greatly decrease the yield of acetylsulfaguanidine.

A number of methods can be used to circumvent the above difficulty. Theacetylsulfanilylchloride can be separated by centrifuging and then ovendrying at 25 to 40 C. This method has the disadvantage of requiring anexpensive centrifuge that is corrosion resistant to hydrochloric acid.Furthermore there is considerable labor and equipment required in theoven drying. Care must be taken in the oven drying of the crude materialsince there is a strong possibility of decomposition.

The prior art makes use of the method of dissolving the crude acidchloride in ether, separation of the water and subsequent precipitationby another organic liquid such as benzene. However, this method is notsatisfactory on a commercial scale because of the multiplicity ofoperations, the hazard involved in the use of diethyl ether, the loss onrecovery and separation of the solvents and the loss of acid chloridedue to the solvents employed.

Good solvents for acetylsulfanilychloride are not numerous. The priorart refers to acetone as such a solvent and acetone has been used forthe purficationyof crude acetylsulfanilylchloride. The crude material isdissolved in the acetone and reprecipitated with water. However, onlyabout 75 percent of the crude material is recovered.

I have discovered, however, that ketones of the type described above arevery good solvents for acetylsulfanilylchloride in a water-wet conditionand may be employed to eifect removal of water from wetacetylsulfanilylchloride and preparationmfasolution'thereofuseableniirectlyl in the condensation-,f processfdescribed-1A above Whereasacetwe La which ,fiszf Water-soluble; is -notsatisfactory for this purpose;V Whenfthe-ketones of the typesenumeratedfabove especially methyl et-hly'` ketone, methyl isobutyl`ketone... and;

mesityl oxide, are.v` stirred; withl .Water-Wet acetylsulanilylchloride4and :preferably Y although notv necessarilyl v with. afk Water-soluble finorganic; salt,-v typiiied by sodium chloride korsodiumsulfate theresulting-v mixture separates into anY aqueous layer .f and .g a ketone1 layer containing the acidt chloride,A If ,such asalt'is used'itfgpesintorsolu-Y tion infthie aqueous phase.v The ketonelayerzcanf beireadilyqo-separated from the aqueous layer y and.

used directlyV for .the condensationV of guanidine..

and; acetylsulfanilylchloride.A The amounts. ofl the, ,ketoneZ and thewater-soluble 4inorganic salt,`r

whereusedyemployedto eiect removal .of- Waterti in thiswayzmay-varyjquite widely but should-bet suiiicient to* achieve-Aseparation ofM at least 90` percent and preferablyas nearly 100percent-as possible -of the Water from-thev acidv chloride. Thefamountofgthe ketone usedv should be suffi-V cient, to dissolve all ofthe acidchlorides The amountgof. the sodium; chloride; sodium sulfate orthelikezshould besufiicient to break; up any emulsionsandlpermit rapidsettling ofthe mixe ture f into two layers..

withresulting loss thereof; In practice I .prefer to .employ an amountof the -ketoneat least equaly to the weightoftheacidfchloride/(calculated on thedry basis) andjstillmore-preferably Iuse plierie,` i. e., from to 30P C. The use of. acetone orV diethyletheri-as a solvent for the preliminary removal ofv waterfromacetylsulfanilylchloride is not -satisfactoryvbecause theseorganicliquids are notgood 4reaction,.media for. the )condensationreaction.` In `anyoase, acetone, is: Water-solubleY and hence couldnotlbe-usedas. ardrying meansu The use of the relativelyVWater-immiscible ketones of my invention;v typified by methyl ethylketone, methyl isobutyl ketone. and mesityl oxidef is` highly:advantageous` because these ketones are: excellent;solventsfor the acidchloride, are superior reaction mediafor the condensation reaction andsince ,they are relatively `Waterinsoluble they can be used `effectivelyfor: removing. .moisture .from the wetacid chloride. The. use of theserelatively water-immiscible :ketones4 for the preliminary removal ofwater from the acetylsulfanilylchloride has the.v further ad? Vantagethat the resulting solutionintheketone. enables-the. addition of the.acid ,chloride to be made more convenientlyiand. uniformly, leading tobetter resultsin the condensation.V Since vthe relativelyxWater-immiscible ketones Vare `used ,as

reaction media when carrying out the condensa--v tion in the mannerdescribed above, there isino. diclult'y such as wouldv be encounteredinthe. use of more than one organic solvent Vand lthe need for. separation4cttwc solvents lis obviated,

Ifh'ave' foundrthat the qualityof the acetylsulfanilylohloridelhasanimportant-eiect on the. yield of .the acetylsulfaguanidine. Since.the.

acetylsulfanilylcliloride is; unstable, especially I in.

It also; serves to reduceY the solution of the ketone inthe aqueousYphase The amount of the aecrude forswetrstateeiteis-eadvisable r`to.use .vit soon: esi'ppssiblefin-:the.condensationrreactionf- If;

vforfany 'reasonfuse offthe acid-:chloridewithin a..

short timezis not `feasible.;v it Aisxadvisable to purifyy itinany,suitablermanner beforestoring it.V I

Sinceithe ketones.,useddn. accordance with the present..invention,4 have3a boiling.; point below' 60 C. at.20 mm.fand:areremovedfbydistillationat sucht-lowtemperatures. .thereE will .not .be any. tendency-for,condensationoof. the .ketone inthev alkaliesuch: las.: would :occur at.higher temperatimes.t Furthermore sde'composition of the acetyl--rsulfaguanidine beyond-,hydrolysis-is avoided. Y

It t.will-be .understood .that since the ketonerecoveredbydistillationthe reaction mixture .will attainffthetemperature-ot-the boiling.,poix1t for theadurationfof the.ketone,recovery y Theaccompanying,drawingiwillbeself-explanatoryginftheflightof the-foregoingdescription... As. showninf Fig.; 2,. the F,step :of separating vvthe precipitatedacetylsulfaguanidine optional. and. as` indicated 1 above suchseparation is preferably omitted. Y-

Theifollowingjexamples. illustrate myrinvention.

in more-detail4 Iii-'a` 500 cc. -Bineckedaskilequipped withA a.thermometer and-fanI-eicient 'stirrer,= therewasl placedf a =solutionof- -24.0i`.g. (0;60 mole)Y sodium hydroxide pellets-'1in'- 60 cc.Vwater. Tof-this was added=250 ige (05205 i mole)` ofguanidine lnitrateandstir-'ringY was continueduntil' solutionf was completesy Tothe aqueous solution-therewas-added `1190 cc. Lofinethyl'l'ethyl ketoneand` the-mixture' was 4cooled-*tof-10 C. with'stirring. Dry lacetyl#sulfanlyichlride 60.05455 (0.257 inole) Vtlureedeiys old;-wasffaddedover a period of twenty minutes,L with stirring; keeping-thetemperatureof y10" toY 15"-Cf The-reaction mixture became quite-'truckw andwasdilutedvwith-ZOO ce. ofivaterfthirtymin-P utes after v=the=completionof vvthe laddition of -'the acetylsiilfanilylchloride; another: lot Aof`r15) ce. of water was added-thirty minutes"afterthe first 'lot andi thestirring T'fvv-as :stopped-lone f and#enel-halfv hours@Aaft'e'rli'the1feom'pletiejn of the acetyls'ulfa nilylchloride additionsThe-productwvas vfiltered,v Washedewithwaterf-till thefiwashirigs werefree lof alkali fand-f dr'iedi infthe -cveii at 570 Clj Ther-yield was46.7 g'orrSQ-percent of theory, `M. PzilftoV 5%- CSI.'

Inra 50(1' ce.v 3-'iiecked rflask fequlp'ped. witha. thermometerandanefiicient stirrer, there was, placed asolutionof .19.2 (0.48 mole). of.sodium hydroxide-:pellets and20..0A g.-v (0.164. mole). ofguanidinefnitrate' in50 `cc. of Water. After add-,- ingglecc.. of-inethy1.-.isobutyl. ketone and cool-f` ing..,to .1'0.l Clthereewasadded48 g.-of acetyle sulfauilylchloridev P.v 149? C.,. over a period. ofthirty `niin.11tes',.keeping.the temperature at 10"to 15, CgFun lots ofwater of.50 cc., 50cc., 100 ce. andZdOcc. were added. forty-five min.,one hun-L dred. and ivemin., Ioneehundred [and` sixty-five mim, A,andonehiindred ,and ninety-five. minutes after.- completing,.theadditio'mof the acetyl? sulfanilylchloridei., "Ih'esolicit productwasffiltered 01111 lwashed,fired-.0f ,alkali .and ydried in,...the. ovenat ,.70 C.: theyield 'was-.42i2gfror 91 percentof. theoryvMfP 248?l to250"v C. The filtrate was, acidie'd to determine ifi any. bs'{acety1su1fanilylfguanidine was, present but no precipitate;

appeared..

Example 3.--Prepardtionofvsulfaguanidine j 'Io a 500 cm3-necked ilaskequipped with a good mechanical stirrer, and a thermometer, there wasadded a solution of 19.2 g. of pellet sodium hydroxide and-20.0 g. ofguanidine nitrate in 50 cc. of water and 160 cc. of methyl ethyl ketone.After the'mixture was cooled to 10 C. 4 3 g. of acetylsulfanilylchloridewas added over a period of thirty-ve minutes with stirring, keeping thetemperature at to 15 C. Thirty minutes after the addition of theacetylsulfanilylchloride 50 cc. of water was added and this was repeatedafter another thirty minutes. After another flfty minutes the methylethyl ketone was distilled oi at 100 mm. and to the residual slurrythere was added a solution of 25 g. of pellet sodium hydroxide in 150cc. of water. The hydrolysis was carried out at '70 to '73 C. withstirring for two hours. The reaction mixture was then cooled to roomtemperature over thirty minutes, filtered and washed with water. Thesulfaguanidine was dried at 70 C. overnight, the yield being 26.5 g. or75.5 percent of theory. In the mother liquor there appeared on standing1.2 g. of white solid containing inorganic material and which did notmelt up to 265 C. When this material was removed and the filtrateacidied to a pH of 2 to 3 there appeared v0.6 g. of yellowish materialwhich decomposed gradually to a tar at 100 to 200 C.

Example 4-Preparation of sulfaguandine The acetylsulfanilylchloride thatwas used was prepared twenty hours earlier; the sample was removed fromthe filter press and was quite wet since the charge was not air blown ordried in any way. From a determination it was found to contain 60percent moisture. A portion of 120 g. of this wetacetylsulianilylchloride was stirred with 110 cc. of methyl ethyl ketoneand 10 g. of sodium chloride until all the acetylsulfanilylchloride wasdissolved. The mixture was then placed in a separatory funnel and anaqueous layer Weighing 73 g. was removed. To a 500 cc. 3-neck askequipped with an eiiicient air tight stirrer and a thermometer, therewas added a solution of 19.2 g. of sodium hydroxide in 50 cc. water inwhich 20.0 g. of guanidine nitrate was dissolved. After adding 50 cc. ofmethyl ethyl ketone and cooling to 10 to 15 C. there was added from theseparatory funnel the above prepared methyl ethyl ketone solution ofacetylsulfanilylchloride over a period of thirty minutes keeping thetemperature at about C. Stirring was continued for thirty minutes afterthe addition was made and then 50 cc. of cold water was added. Afteranother thirty minutes a further portion of 50 cc. of water was addedand the stirring continued for another hour. In the third neck of thereaction ask there was placed a distillation head and the methyl ethylketone was distilled off with stirring bringing the waterbathtemperature up to 50 C. and keeping the pressure at 110 mm.; the vaportemperature of the methyl ethyl ketone was found to be 30 to 35 C.; themethyl ethyl ketone receiver was kept cold with ice water. When themethyl ethyl ketone was removed there was added a solution of 24.0 g. ofsodium hydroxide in 100 cc. water and the slurry was heated withstirring at 70 C. for ninety minutes. A test aliquot at the end of sixtyminutes was completely soluble in cold dilute acid. At the end of theninety minute period the mixture was cooled to 15 C. over a period oithirty minutes and ltered. The fil- :10 trate had no detectable odor ofammonia indieating little decomposition of the sulfaguanidine. The cakewas washed free of alkali and dried in the oven at 70 C. overnight. Theyield was 26.4 g. or 75 percent M. P; 184 C.

Example 5-Preparatz'on of sulfaguamdine To a 500 cc. 3-necked ilaskequipped with a stirrer and a thermometer, there was added a solution of19.2 g. of sodium hydroxide and 20.0 g. of guanidine nitrate in 50 cc.water, and then 150 cc. ol mesityl` oxide. After cooling to 10 C., 48.0g. of acetylsulfanilylchloride was added over a period of twenty-livevminutes. Twenty minutes after-the addition o f theacid chloride 50 cc.oi water was added; thiswas repeated after another -twenty minutes-After another forty minutes stirring the mesityl oxide was distilled offunder vacuum recovering 134 cc. or about 90 percent of the originalsolvent used. To the remainder in the reaction flask there was added cc.of water and a solution of 24 g. of sodium hydroxide in 50 cc. water.The mixture was stirred with heating for two hours at 70 to 78 C.,allowed to cool and the sulfaguanidine was nltered off and washed freeof alkali. The yield after drying at 70 C. was 63 percent of theory M.P. 186 C.

From the foregoing description many advantages of the present inventionwill be apparent to those skilled in the art. The principal advantage isthat the process of the present invention improves the yield ofacetylsulfaguanidine from around 70 percent to around 90 percent. Thisimprovement in yield is effected primarily by the use of the selectedketones of the present invention and the use of an excess of theacetylsulfanilylchloride in the condensation with guanidine. Anotheradvantage of the present invention is that it provides a much simplifiedprocess whereby the condensation of guanidine andacetylsulfanilylchloride and the hydrolysis of the acetylsulfaguanidineare conducted in a single continuous process which eliminates theisolation of the intermediate. This not only saves much labor, rawmaterials and equipment, but increases the productivity and avoids thedifficulty of illtering off the very iinely precipitatedacetylsulfaguanidine which was a serious problem in prior art practice.The process described herein provides for the recovery of nearly all ofthe ketone used as the solvent, thereby greatly reducing costs. Inaddition the method described herein enables the removal of water fromacetylsulfanilylchloride to be elected in a simple and economicalmanner. The removal of moisture from water-wet acetylsulfanilylchloridewas a very serious problem until the method described herein wasdiscovered.

This application is a division of my application Serial No. 19,703,i'lled April 8, 1948.

Having thus described my invention, what I claim and desire to protectby Letters Patent is:

1. The process of removing water from waterwet pacetylsulfanilylchloridewhich comprises admixing the same with a ketone having the generalformula where R is a group selected from the class consisting of C2 toC4 alkyl and alkenyl groups, allowing the resulting mixture to separateinto an aqueous layer and a ketone layer and separating said ketonelayer from said aqueous layer, said

1. THE PROCESS OF REMOVING WATER FROM WATERWETP-ACETYLSULFANILYLCHLORIDE WHICH COMPRISES ADMIXING THE SAME WITH AKETONE HAVING THE GENERAL FORMULA